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The effects of palbociclib on 2d and 3d cell cultures and doxorubicin resistance

Yalçın, Gizem Damla
Cell culture facilitates studying the mechanism of diseases and finding new treatment strategies. Traditionally used two­dimensional cell culture model is not quite sufficient in some studies due to the factors such as lack of cell to cell and cell­extracellular matrix interactions and changing cell morphology. Because of the limitations in 2D cell culture, nowadays three­dimensional cell cultures gain importance. The present study aims to identify the effect of Palbociclib on different cells when they cultured 2D and 3D. Palbociclib is a dual cyclin-dependent kinase 4 and 6 inhibitor. Palbociclib has been shown to be effective against tumor cells administered alone or in combination, and it has widely been studied in breast cancer cell lines. However, its role in 3D culture of breast cancer cells which is the closest culture model mimicking tumor tissue has not totally been examined by regarding diverse subtypes of breast cancer cell. The results underlined that MCF-7 and SKBR-3 cells which was capable of forming 3D spheroid structure more resistant to Palbociclib according to cell viability analysis. Additionally, the effect of Palbociclib was different between these two approaches in terms of cell cycle distribution and gene expression analysis, which demonstrated the importance of 3D culturing that was performed by Hanging drop method during the molecular pharmaceutical studies. Palbociclib was also evaluated in doxorubicin-resistant cells with diverse tumor origin. Resistance to anticancer agents is the main obstacle of the success of the chemotherapy. The ABC-transporter MDR1/P-glycoprotein (MDR1/P-gp; ABCB1), which was the first defined factor, lies behind the multidrug resistance. The using of multiple anti-cancer agents in combination, which is resensitized the cell to drug, has come into prominence to treat drug resistance in cancer. The results revealed that when the Doxorubicin combined with Palbociclib, the IC50 values of Doxorubicin significantly decreased in MCF-7/DOX, HeLa/DOX, K562/DOX and SKBR-3 cells, which had MDR-1 gene expression. Moreover, Palbociclib re-sensitized the resistant cells towards doxorubicin by down-regulating the P-gp, which was the principal mechanism supporting the doxorubicin resistance in these cell lines. The results clarified that Palbociclib could be a critical agent for combination therapy in the treatments of Doxorubicin-resistant cancer types. Further molecular and clinical studies are needed to totally explore the influence of Palbociclib in cancer and cancer drug resistance.